ABSTRACT. Pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)) is an acquired autoimmune disease in which IgG antibodies target the keratinocyte desmosomal cadherin proteins desmoglein-3 and desmoglein-1, resulting in intraepithelial, mucocutaneous blistering. Nearly all PV and PF patients (96%? 100%), but no unaffected individuals, demonstrate detectable anti-DSG3 and anti-DSG1 reactivity, respectively. PV is a potentially fatal autoimmune disorder with a mortality rate of 75% on average without treatment with corticosteroids. Current methods for pemphigus treatment require general immune suppression to reduce overall antibody production, but this approach impairs protective immune responses, which can lead to potentially fatal infections and secondary cancers. We propose a novel approach for targeted immunotherapy of PV by directing patient's T cells to specifically seek out and kill the pemphigus-specific B cells, while sparing the beneficial immune cells that protect from infection. As a proof-of-principle, in phase I, Multi-specific T-cell Engagers or MuTE ? IgG-like recombinant proteins consisting of a well-characterized anti-CD3 antibody OKT3 with mutated human IgG4 Fc, and human desmoglein-1 and desmoglein-3 extracellular domains will be produced. The T-cell mediated target elimination of anti-desmoglein specific B cells by MuTE will be validated in cell-based assays and in mouse models. Phase II work will focus on scale-up of biologics production, obtaining the preclinical in vivo pharmacodynamics, pharmacokinetics and toxicity data in animal models necessary for submission of an IND.